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HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance.
- Source :
-
Blood [Blood] 2000 Apr 01; Vol. 95 (7), pp. 2378-85. - Publication Year :
- 2000
-
Abstract
- Multidrug resistance (MDR) is often characterized by the expression of P-glycoprotein (P-gp), a 170-kd ATP-dependent drug efflux protein. As well as effluxing xenotoxins, functional P-gp can confer resistance to caspase-dependent apoptosis induced by a range of different stimuli, including Fas ligand, tumor necrosis factor, UV irradiation, and serum starvation. However, P-gp-positive cells remain sensitive to caspase-independent death induced by cytotoxic T-cell granule proteins, perforin, and granzyme B. It is, therefore, possible that agents that induce cell death in a caspase-independent manner might circumvent P-gp-mediated MDR. We demonstrated here that hexamethylene bisacetamide (HMBA) induced equivalent caspase-independent cell death in both P-gp-positive and -negative cell lines at concentrations of 10 mmol/L and above. The HMBA-induced death pathway was marked by release of cytochrome c from the mitochondria and reduction of Bcl-2 protein levels. In addition, we show that functional P-gp specifically inhibits the activation of particular caspases, such as caspases-8 and -3, whereas others, such as caspase-9, remain unaffected. These studies greatly enhance our understanding of the molecular cell death events that can be regulated by functional P-gp and highlight the potential clinical use of drugs that function via a caspase-independent pathway for the treatment of MDR tumors.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 analysis
ATP Binding Cassette Transporter, Subfamily B, Member 1 pharmacology
Caspase 9
Cytochrome c Group metabolism
Enzyme Activation drug effects
Humans
Leukemia-Lymphoma, Adult T-Cell metabolism
Leukemia-Lymphoma, Adult T-Cell pathology
Mitochondria drug effects
Mitochondria metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Tumor Cells, Cultured
ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology
Acetamides pharmacology
Apoptosis drug effects
Caspases metabolism
Drug Resistance, Multiple
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 95
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 10733510